Human Heredity 11th Edition by Michael Cummings

Exercise 5

PKU
Phenylketonuria (PKU), the recessively inherited genetic disorder of amino acid metabolism, is regarded as the gold-standard genetic disorder. Its discovery in 1935 laid the foundation for human biochemical genetics. Knowledge about PKU encompasses almost every area and most of the technology of human genetics. The three-dimensional structure of the enzyme (phenylalanine hydroxylase, or PAH) responsible for the disorder is known, and its regulatory, catalytic, and binding sites have been mapped. Additionally, the PAH gene has been cloned and its mutational sites identified. Biochemical defects and behavioral deficits in PKU and the correlation between genotype and phenotype are well known, and the risks to genotypically normal fetuses carried by affected females are recognized. The disorder can be diagnosed prenatally, a treatment that prevents intellectual disability is available, and a newborn-screening program is used throughout the developed world to detect and treat affected individuals. An animal model with a matching biochemical phenotype has been developed and used to study changes in brain structure, gene expression, and metabolism in this disorder.
PKU seems to be a straightforward disorder caused by a mutant allele encoding a defective enzyme, but the disorder has complexities still being revealed. In rare cases, the PAH gene is normal, but mutations in at least four genes encoding the enzyme's cofactor, BH4, cause PKU. Recent work using a mouse PKU model suggests that elevated blood levels of phenylalanine trigger changes in levels of PAH expression and the expression of other genes, creating a unique metabolic environment in the brain that plays a role in the phenotype. Dietary treatment with a nutritional supplement has been used for decades, but it is unpleasant in taste and has personal, social, and financial costs. Methods such as enzyme encapsulation have proven to be unsatisfactory, and gene therapy and liver transplantation have risks that far exceed the benefits of replacing a dietary supplement. Strategies for reducing blood levels of phenylalanine using yeast enzymes to metabolize the amino acid have not been successful. A new diet based on GMP, a protein by-product of cheese production with only trace amounts of phenylalanine, is showing promise. In addition, a drug (Kuvan) based on BH4 is effective in reducing blood levels of phenylalanine in some cases. The wide-ranging research on PKU is a reminder that the social impact of genetics remains one of the most unexplored areas of this science.
If you were born in the United States or many other countries in the last 30 years, you were tested for PKU, and are a beneficiary of and participant in the genetic revolution that is part of human genetics.
The amino acid tyrosine is synthesized from phenylalanine. Does this make tyrosine an essential amino acid in individuals with PKU?